Does an endogenous methylpyridinium analogue cause Parkinson's disease?
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
B Costall
Publications and source records attributed to B Costall.
A comparison of dopamine agonist action to inhibit locomotor activity and to induce stereotyped behaviour in the mouse.
51 purported dopamine agonists from the phenylethylamine, tetralin, octahydrobenzo(f)- and (g)quinoline, benzocycloheptene, aporphine and ergoline series were tested in the mouse for ability to cause motor inhibition at low doses and stereotyped responding (motor facilitation) at higher doses. Motor inhibition was characterised either by a freezing akinesia (spiroperidol sensitive) or by sedation (resistant to spiroperidol). Agents potent to induce the freezing response could, if the dose was raised sufficiently (at least 10 fold), cause stereotypy. Within all series tested N-n-propyl substitution generally conferred greatest selectivity of motor inhibitory action. Radioligand binding assays using [3H]ADTN as ligand and rat striatal tissue showed correlations between abilities to associate with the dopamine receptor and to cause motor inhibition or facilitation, but discrepancies were apparent, particularly within the tetralin series. It is concluded that whilst there exists clear potency differences to inhibit locomotor activity and to induce stereotyped behaviour, it is difficult to demonstrate unequivocally an absolute selectivity of dopamine agonist action for the motor inhibitory dopamine system.
Animals↗
Neuronally mediated contraction responses of guinea-pig stomach smooth muscle preparations: modification by benzamide derivatives does not reflect a dopamine antagonist action.
The actions of the substituted benzamide derivatives metoclopramide, clebopride, YM-09151-2, tiapride, (+)- and (-)-sulpiride and (+)- and (-)-sultopride, and the dopamine antagonists haloperidol and domperidone, were studied on the responses to field stimulation (0.125-10 Hz) of smooth muscle strips taken from cardia, fundus, body and antral regions of the longitudinal and circular muscle of guinea-pig stomach. Field stimulation of the longitudinal strips caused contraction responses which were antagonised by atropine (but not by prazosin, yohimbine, propranolol or methysergide) to indicate a muscarinic cholinergic involvement. Antagonism of the contractions revealed or enhanced relaxation responses mediated via unidentified mechanisms (resistant to cholinergic and adrenergic antagonists). Metoclopramide enhanced the field stimulation-induced contractions of the stomach smooth muscle preparations via atropine sensitive mechanisms but failed to attenuate the field stimulation-induced relaxation responses. Clebopride's action closely followed that of metoclopramide but YM-09151-2 only enhanced the contraction responses of the longitudinal muscle preparations. Other dopamine antagonists, (+)- and (-)-sulpiride, (+)- and (-)-sultopride, tiapride, haloperidol and domperidone failed to facilitate contraction to field stimulation of any stomach tissue. Thus, the actions of metoclopramide, clebopride and YM-09151-2 to facilitate contraction to field stimulation of stomach smooth muscle are mediated via a muscarinic cholinergic mechanism and are not the consequence of an antagonism at any recognisable dopamine receptor.
Animals↗
Locomotor hyperactivity caused by dopamine infusion into the nucleus accumbens of rat brain: specificity of action.
Rats selected as high-activity and low-activity responders to the hyperactivity-inducing action of peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subject to intra-accumbens infusion of dopamine, noradrenaline, serotonin, acetylcholine and GABA (0.48 microliters/h, 25 micrograms/24 h, 13 days). Locomotor activity was measured during infusion and for a minimum of 35 days thereafter. After discontinuation of infusion the animals' responsiveness to (-)NPA was also assessed and, on the 2nd day of withdrawal, sensitivity to the hyperactivity-inducing action of acute intra-accumbens dopamine was determined. Dopamine caused a biphasic pattern of hyperactivity during infusion with peaks of responding between days 2-5 and 8-12: normal values returned after withdrawal of infusion. However, 2-3 weeks after withdrawal of intra-accumbens dopamine infusion animals showed reversed responding to (-)NPA challenge, the initial low-active animals giving a high-active response and high-active animals giving low-activity. Infusions of noradrenaline, serotonin, GABA and acetylcholine produced some increase in locomotor activity towards the termination of infusion, but no treatment could replicate the first hyperactivity peak and no treatment, after withdrawal, could reverse the responsiveness to (-)NPA of high- and low-active animals. Acute injections of dopamine into the nucleus accumbens showed that the infusion of the different neurotransmitter substances caused change within that nucleus. Nevertheless, changes in locomotor behaviour following the infusion of dopamine into the nucleus accumbens are specific for dopamine.
Acetylcholine↗
The mechanism of action of dopamine to inhibit field stimulation-induced contractions of guinea pig stomach strips.
Field stimulation (0.125-10 Hz) of longitudinal smooth muscle strips taken from the fundus of guinea pig stomach caused frequency related contraction responses (atropine-sensitive) associated with relaxation at the higher frequencies (both responses tetrodotoxin-sensitive). Dopamine, noradrenaline, adrenaline and apomorphine antagonised the contraction responses at all frequencies; the concentration-response curves were steep and the use of higher concentrations was precluded by changes in base line tension per se. That noradrenaline was approximately 10 fold more potent than dopamine, that the dopamine response was not antagonised by the dopamine antagonists haloperidol, domperidone or (-)sulpiride, but was mimicked by the alpha 2-agonist guanfacine and partially antagonised by the alpha 2-adrenoceptor antagonist yohimbine (which could also antagonise the inhibitory actions of guanfacine) would indicate that a component of dopamine's action to reduce cholinergic activity is effected via alpha 2-adrenoceptor mechanisms. A failure of phenylephrine to mimic, or prazosin to attenuate the agonist inhibitory responses would not indicate an additional alpha 1-adrenoceptor involvement. The persistence of the dopamine response following disruption of noradrenergic function by reserpine or inhibition of catecholamine reuptake processes (desmethylimipramine plus corticosterone, GBR 13098) would indicate a direct action of dopamine. It is concluded that the ability of dopamine to reduce cholinergic induced contractions in longitudinal smooth muscle of the stomach does not reflect a dopamine receptor or alpha 1-adrenoceptor stimulation but may involve an action on alpha 2-adrenoceptors.
Animals↗
Unilateral striatal dopamine denervation: reduced motor inhibitory effects of dopamine antagonists revealed in models of asymmetric and circling behaviour.
Circling and asymmetric behaviours to apomorphine (dopamine agonist/antagonist) challenge were studied in rats with unilateral striatal electrolesions or 6-hydroxydopamine (6-OHDA) lesions, each induced by combined lesions at 3 striatal locations, to allow an assessment of drug action on 'normal' receptors in the intact striatum or 'supersensitive' receptors in the lesioned striatum respectively. The minimally effective dose of 6-OHDA (given in the presence of DMI and tranylcypromine) to cause functional change was 3 X 8 micrograms, with 3 X 32 micrograms providing maximal change. Electrolesions were shown histologically to be confined to striatal tissue, and dopamine depletions caused by 6-OHDA were selective for the striatum. Temporal differences were recorded for onset of asymmetry and circling behaviour, both between behaviours and between lesions. Thus, asymmetry developed during the 2nd-4th days after 6-OHDA lesion but circling developed more abruptly on postoperative days 10-12. In contrast, both asymmetry and circling behaviours were apparent from the first day following electrolesion. The dose-dependent effects of apomorphine were apparent at much lower doses in 6-OHDA lesioned than electrolesioned rats. This potency difference was also demonstrated for two further dopamine agonists, 2-di-n-propylamino-5,6-dihydroxytetralin and SK & F 38393. In contrast, the agonist-induced asymmetric and circling behaviours of electrolesioned rats were some 9-44 times more sensitive than those of 6-OHDA lesioned rats to antagonism by the neuroleptic agents haloperidol, alpha-flupenthixol and oxiperomide, although tiapride antagonism was very similar in both the electrolesioned and 6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Inhibition and facilitation of motor responding of the mouse by actions of dopamine agonists in the forebrain.
The actions of dopamine and agonists of dopamine to influence forebrain structures and modify spontaneous locomotion of the mouse were studied, firstly, by injecting agents from different chemical series into the nucleus accumbens (phenylethylamine, aporphine, benzo[g]quinoline, tetralin, dopamine, N-n-propyl-N-phenethyldopamine, N-n-propyl-N-butyldopamine, apomorphine, trans-N-n-propyl-6,7- and -7,8-dihydroxyoctahydrobenzo[g]quinoline, 2-di-n-propylamino-5,6- and -6,7-dihydroxytetralin, 2-di-ethylamino-5,6-dihydroxytetralin) and, secondly, by selecting a potent agent (2-di-n-propylamino-5,6-dihydroxytetralin) for injection into 43 other forebrain areas. Agents from all chemical series were shown to reduce locomotor activity on injection into the nucleus accumbens. The most effective agents were the dialkylated tetralin derivatives and the N-propyl benzo[g]quinoline compound (0.025-0.5 micrograms); inhibition of motor activity generally decreased as dose was increased. The inhibitory effects on motor activity of the propyl substituted tetralin and [g]quinoline were specifically antagonised by sulpiride and/or spiperone (prazosin, yohimbine and methysergide were ineffective). Injections of tetralin (0.1 micrograms) not only into the nucleus accumbens but also into the tuberculum olfactorium, septal nucleus, anterior olfactory nucleus, anteromedial fibre system, claustrum and caudate-putamen could effect inhibition of motor activity. Generally, injections away from these structures were ineffective. It is suggested that small doses of dopamine and agonists of dopamine can influence dopamine receptors which are sensitive to neuroleptic drugs (presynaptic in limbic and striatal regions, but with a possibility of postsynaptic involvement in cortical regions) to effect inhibition of motor activity from a number of discrete areas of the forebrain of the mouse.
Animals↗
Long-term consequences of antagonism by neuroleptics of behavioural events occurring during mesolimbic dopamine infusion.
Rats selected as low-activity responders to peripherally administered (-)N-n-propylnorapomorphine [(-)NPA] were subjected to a 13-day continuous infusion of dopamine bilaterally into the nucleus accumbens (0.48 microliter/hr, 25 micrograms in 24 hr). This caused biphasic increases in spontaneous levels of hyperactivity with peaks occurring between days 2-5 and 8-12 of infusion. Two weeks after the infusion was withdrawn the low-activity status of the animals, to (-)NPA challenge, converted to high-activity and remained at this changed level for 18 to 20 weeks. The effects of sulpiride (2.5 mg/kg, i.p. daily) or haloperidol (0.025 mg/kg, i.p. daily) on the behavioural changes during infusion and after its withdrawal were assessed by administration on days 1-4 to inhibit the first peak of the enhanced spontaneous locomotion, on days 8-11 to inhibit the second peak, on days 1-4 and 8-11 to inhibit both peaks, on days 6-9 to influence the "trough" of behavioural responding between the peaks of hyperactivity, and on days 1-11 to modify all components of hyperactivity responding to infusion of dopamine. The usual consequence of infusion, the conversion of low-activity to high-activity responders to (-)NPA, was not prevented by any treatment with neuroleptic. It is concluded that the long-term consequences (up to 1 year) of a brief period (13 days) of overactivity induced by mesolimbic infusion of dopamine cannot be prevented by daily treatment with haloperidol or sulpiride in doses adequate to prevent the behavioural expression of the effects of the dopamine stimulation during its infusion.
Animals↗
The antidyskinetic action of dihomo-gamma-linolenic acid in the rodent.
The antidyskinetic action of dihomo-gamma-linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea-pig by dopamine injected into the striatum (200 micrograms bilateral 2 h after nialamide, 75 mg kg-1, i.p.) and in the guinea-pig and rat by 2-di-n-propylamino-5, 6-dihydroxytetralin (tetralin), 0.025 mg kg-1, s.c. Dopamine and tetralin-induced dyskinesias in the guinea-pig were reduced or abolished by DHLA given i.p., 30-100 mg kg-1, given once daily for 5-10 days. Tetralin-induced dyskinesias were antagonized by DHLA given orally to the guinea-pig (50-200 mg kg-1, 5 days) or in the diet to the rat (approximately 200 mg kg-1 daily for 10-14 days). DHLA injected into the striatum (2.5-20 micrograms bilateral, 2-4 days) also antagonized tetralin-induced dyskinesias in the rat. The antidyskinetic action of DHLA given i.p. to the guinea-pig could be antagonized by aspirin or eicosa-5,8,11,14-tetraynoic acid (100 mg kg-1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25-100 mg kg-1, i.p.) dose-dependently antagonized the antidyskinetic activity of 5 and 20 micrograms DHLA given bilaterally into the striatum (2 days). DHLA (100 mg kg-1 i.p.) given daily for 10 days or approximately 200 mg kg-1 DHLA (daily for 10-14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg-1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg-1 i.p. 7 It is suggested that the selective inhibition of dyskinesias in the rodent by DHLA may reflect a striatal effect with a dependency on conversion to prostaglandins.
5,8,11,14-Eicosatetraynoic Acid↗
SCH 23390 can enhance field stimulation-induced contractions of longitudinal smooth muscle from guinea-pig stomach.
Field stimulation-induced contractions of guinea-pig stomach longitudinal muscle strips were enhanced by metoclopramide (a D-2 receptor antagonist) and SCH 23390 (a D-1 receptor antagonist) but not by cis-flupenthixol (a D-1 and D-2 receptor antagonist) or sulpiride (a D-2 receptor antagonist). SCH 23390 is the first non-benzamide neuroleptic drug shown to enhance cholinergic mediated contraction responses of gastric smooth muscle, but the response does not appear to reflect a D-1 receptor antagonism.
Animals↗
The mesolimbic nucleus accumbens is critically involved with the mediation of the motor inhibitory and facilitatory effects of dopamine agonists on mouse spontaneous climbing behaviour.
Mouse spontaneous climbing behaviour was dose-dependently inhibited by putative dopamine agonists administered subcutaneously (s.c.) or directly into the mesolimbic nucleus accumbens. ED50 values for s.c. administrations of apomorphine, bromocriptine, DPI, 3-PPP and DK118 (5-hydroxy-6-methyl-2-di-n-propylaminotetralin) were 0.01, 0.26, 0.17, 0.24 and 0.0004 mg/kg respectively, and for intra-accumbens apomorphine, DPI, bromocriptine, DK118 and 2-di-n-propylamino-5,6-dihydroxytetralin were 0.21, 0.22, 7.5, 0.00034 and 0.000034 micrograms respectively. Dose-dependent reduction in motor inhibitory potential/motor facilitation was also recorded for higher doses of apomorphine given s.c., or for apomorphine, DK118 and 2-di-n-propylamino-5,6-dihydroxytetralin given intra-accumbens (ED50 values to restore spontaneous climbing to control values were 4.1, 4.2 and 0.8 micrograms respectively). The motor inhibitory actions of apomorphine, 3-PPP, DK118 and 2-di-n-propylamino-5,6-dihydroxytetralin were antagonised by (-)-sulpiride, but not by yohimbine or prazosin. The actions of DPI were yohimbine-sensitive. Whilst the motor inhibition caused by s.c. bromocriptine was neuroleptic-sensitive, that observed on intra-accumbens injection was resistant to all antagonists. The intra-accumbens effectiveness of the dopamine agonists could not be mimicked by injections above the nucleus accumbens (into the head of the caudate-putamen complex) or below the nucleus accumbens (into the tuberculum olfactorium) (with the exception of the effectiveness of bromocriptine administered into the tuberculum olfactorium). It is suggested that the actions of 'dopamine agonist' to both inhibit and facilitate mouse spontaneous climbing behaviour involves an action in the mesolimbic nucleus accumbens. Whilst the mechanisms involved are generally neuroleptic-sensitive, alpha 2-adrenoceptor (for DPI) and other unidentified mechanisms (for bromocriptine) may also be important.
Animals↗
The production of asymmetry and circling behaviour following unilateral, intrastriatal administration of neuroleptic agents: a comparison of abilities to antagonise striatal function.
The abilities of typical and atypical neuroleptic agents to antagonise at striatal dopamine receptors were determined in the rat. Neuroleptic agents were injected unilaterally into the striatum and asymmetric body posturing/circling behaviour (always ipsilateral to the side of neuroleptic injection) assessed (1) to neuroleptic challenge alone (vehicle injected into the contralateral striatum), (2) as that revealed after neuroleptic challenge by peripherally administered apomorphine or (3) by dopamine injection into the contralateral striatum. Unilateral intrastriatal fluphenazine (1-5 micrograms), cis- and trans-flupenthixol (1-20 micrograms), haloperidol (0.5-5 micrograms), thioridazine (5-10 micrograms), clozapine (1-5 micrograms), tiapride (1-5 micrograms), metoclopramide (1-10 micrograms), (+)-sulpiride (20 micrograms) and piperoxan (10 micrograms) each failed, alone, to cause any postural asymmetry/circling. However, ipsilateral asymmetry was induced by unilateral intrastriatal (-)-sulpiride (1-5 micrograms). In contrast, ipsilateral asymmetry developed when the intrastriatal injection of all neuroleptic agents (excepting (+)-sulpiride and trans-flupenthixol) was followed by peripheral challenge with apomorphine: effective neuroleptic doses were all in the range 0.5-10 micrograms, although (-)-sulpiride was effective at 0.001-0.1 microgram. Active circling was only recorded for (-)-sulpiride and tiapride. The striatal imbalance caused by (-)-sulpiride could be revealed by apomorphine for 24 h, although other intrastriatal neuroleptic responses persisted for 6-8 h. The abilities of all neuroleptic agents to cause striatal imbalance could also be revealed by injecting dopamine into the contralateral striatum (at a dose which alone did not cause any asymmetric motor responding). These intrastriatal injection approaches are forwarded as valuable techniques for determining striatal dopamine antagonist activity in the rodent.
Animals↗
A central site of action for benzamide facilitation of gastric emptying.
Gastric emptying of the fed guinea-pig was measured using a non-invasive X-ray fluoroscopic technique to determine passage from the stomach of polystyrene-coated barium sulphate spheroids. Peripherally administered metoclopramide (0.1-10 mg/kg i.p.), clebopride (1-10 mg/kg i.p.), (-)-sulpiride (40 mg/kg i.p.), haloperidol (1 mg/kg i.p.) and domperidone (1-10 mg/kg i.p.) failed to modify gastric emptying. Stress inhibited emptying, and this was considered to explain the effects of eserine and high dose metoclopramide. Gastric emptying was decreased by peripherally administered atropine (0.5 mg/kg i.p.) and apomorphine (0.1-0.5 mg/kg s.c.); the apomorphine response was antagonised by pretreatment with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride but not by prazosin + propranolol. Gastric emptying was facilitated by intracerebroventricular (i.c.v.) administrations of metoclopramide and clebopride (40, 100 and 200 micrograms) but not by i.c.v. domperidone, haloperidol, fluphenazine or (-)-sulpiride (100, 200 micrograms) and was inhibited by i.c.v. apomorphine (100, 200 micrograms); the response to i.c.v. apomorphine was antagonised by i.c.v. pretreatments with haloperidol, domperidone, (-)-sulpiride, metoclopramide and clebopride (40-50 micrograms). Facilitation of emptying by i.c.v. metoclopramide was prevented by peripheral pretreatment with atropine (0.5 mg/kg i.p.). It is concluded that the actions of apomorphine and metoclopramide/clebopride to respectively inhibit and facilitate gastric emptying may be mediated, at least in part, via central mechanisms. Whilst apomorphine's action may be mediated via dopamine receptor mechanisms, metoclopramide and clebopride act at additional unspecified sites, metoclopramide's action being expressed via cholinergic mechanisms.
Animals↗
Stimulation of rat spontaneous locomotion by low doses of haloperidol and (-)-sulpiride: importance of animal selection and measurement technique.
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Animals↗
Field stimulation-induced responses of circular smooth muscle from guinea-pig stomach. Characterisation of the receptor mechanisms involved.
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Animals↗
A comparison of the behavioural consequences of chronic stimulation of dopamine receptors in the nucleus accumbens of rat brain effected by a continuous infusion or by single daily injections.
Mesolimbic dopamine (DA) receptors of the rat were subject to a chronic (13 day) stimulation effected either by single, repeated daily injections or by infusion from osmotic minipumps of 1.56-50 micrograms DA bilaterally into the nucleus accumbens. Rats were preselected according to their responsiveness to the hyperactivity inducing effect of the DA agonist (--)N-n-propylnorapomorphine [(--)NPA], and the two groups categorised as 'high' and 'low' activity responders were used in the present studies. Whilst the stimulation of mesolimbic DA receptors by a single acute injection or by a 24 h infusion was ineffective to modify locomotor responding, the repetition of the daily injections or the continuation of the infusion caused dose-related increases in locomotor activity of both groups of rats. The spectrum of enhanced activity responding depended on the mechanism of stimulation, a 'biphasic' or 'monophasic' pattern resulting from the infusion or daily injections respectively. It was an important observation that a repetitive biting behaviour developed concomitant to the hyperactivity during daily DA injections, a response not observed during infusion, indicating that the nature of the receptor stimulation, continuous or pulsatile, can dictate the development of a motor response. The effects of discontinuing the chronic intra-accumbens stimulation on responsiveness to (--)NPA was the same whether the chronic stimulation was achieved by repeated injection or infusion. However, the consequences of DA withdrawal critically depended on the initial classification of rat activity according to (--)NPA. Thus, initially 'high' response animals developed a 'low' sensitivity whilst initially 'low' sensitive animals reversed to 'high' responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduction in motor responding of the mouse by actions of dopamine agonists in the midbrain.
Mice were implanted stereotaxically with chronically indwelling bilateral guide cannulae to allow the intracerebral injection of dopamine or the dopamine agonist 2-di-n-propylamino-5,6-dihydroxytetralin into the centre of the substantia nigra, above the substantia nigra or anterior and posterior to the nigra. The intranigral injection of dopamine and the tetralin compound could be shown to dose-dependently reduce the spontaneous locomotor activity of mice. The effectiveness of dopamine decreased with a delayed onset when injections were made anterior or posterior to the substantia nigra; this spectrum of reduced and delayed responding was also apparent when dopamine and the tetralin compound were injected 1 or 2 mm above the nigra. The inhibitory action of dopamine on motor activity, when injected into the substantia nigra, was antagonised by a small dose of spiroperidol which did not influence spontaneous locomotor responding in its own right; prazosin and yohimbine were ineffective. It is suggested that the inhibitory actions of dopamine and 2-di-n-propylamino-5,6-dihydroxytetralin on motor activity may reflect an ability to stimulate dopamine "autoreceptors" in the midbrain area containing the dopamine cell bodies which innervate striatal and mesolimbic forebrain regions.
Animals↗
Does contralateral circling involve action of drugs on hyposensitive striatal dopamine receptors in the hemisphere contralateral to denervation?
Rats receiving unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA) (3 x 16 micrograms, in the presence of tranylcypromine and desmethylimipramine (DMI), resulting in 84% dopamine depletion) exhibited contralateral asymmetry and circling behaviour on peripheral challenge with apomorphine or on unilateral intrastriatal injection of dopamine (into the denervated striatum) (resulting in a stable response after 8 days). The denervated striatum was markedly more sensitive to the effects of dopamine than the normal striatum, although dopamine failed to elicit a response from an intact striatum opposite to a denervation by 6-OHDA. Following unilateral striatal electrolytic lesions (resulting in a stable response after 6-8 days) the rats exhibited ipsilateral asymmetry and circling after the apomorphine challenge. Again, the striata opposite to the lesion failed to mediate a response to dopamine. The contralateral responses to apomorphine observed in animals lesioned with 6-OHDA were not enhanced when an electrolytic lesion was subsequently placed in the intact striatum, nor were the ipsilateral responses of lesioned rats to apomorphine enhanced when 6-OHDA was subsequently injected into the opposite striatum. All asymmetric and circling responses were sensitive to neuroleptics. Thus, it is concluded that a unilateral striatal lesion produced by 6-OHDA or electrolytic lesion can cause reduced functional dopaminergic activity in the opposing striatum. This dopaminergic hyposensitivity would facilitate a contralateral response initiated by hypersensitive mechanisms in the denervated striatum.
Animals↗